Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models
Dominant Genetic Variation and Missing Heritability for Human Complex Traits: Insights from Twin versus Genome-wide Common SNP Models
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DOI：
10.1016/j.ajhg.2015.10.004
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发表时间：
2015-11-05
影响因子：
9.8
通讯作者：
Magnusson, Patrik K. E.
中科院分区：
文献类型：
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作者：
Chen, Xu;Kuja-Halkola, Ralf;Magnusson, Patrik K. E.
为了进一步阐明显性遗传变异在“缺失遗传力”争论中的潜在作用，我们研究了18个人类复杂性状的加性遗传变异（狭义遗传力，h(2)）和显性遗传变异（δ(2)）。在相同的研究基础（10,682对瑞典双胞胎）中，我们计算并比较了经典的基于双胞胎的结构方程模型与基于snp的基因组相关性矩阵限制最大似然[GREML(d)]方法的估计。在双胞胎模型中，δ(2)对14个性状的贡献是明显的(平均δ (2)(twin) = 0.25，范围0.14-0.49)，其中两个性状在GREMLd分析中也显示出显著的δ(2)(甘油三酯δ (2)(SNP) = 0.28，腰围δ (2)(SNP) = 0.19)。平均而言，ade拟合性状的h(SNP)(2)/h(twin)(2)的比例为70%（其最佳拟合模型包括加性遗传和显性遗传以及独特环境成分），ae拟合性状的h(SNP)(2)/h(twin)(2)的比例为31%（其最佳拟合模型包括加性遗传和独特环境成分）。从自我报告的配对内接触频率和分离年龄中获得了来自共同环境贡献的独立证据，也在ade拟合特征中。我们得出的结论是，尽管事实上加性遗传似乎构成了大多数复杂性状的大部分遗传影响，但在双胞胎和家庭研究中，显性遗传变异可能经常被共同环境所掩盖，因此可能比基于家庭的估计所显示的作用更突出。在规模太小的双胞胎研究中，错误地将所有遗传影响（加性和显性）归因于h(2)的风险也可能导致夸大的“缺失遗传性”（h(2)的比例仍未被SNPs解释）。
In order to further illuminate the potential role of dominant genetic variation in the "missing heritability" debate, we investigated the additive (narrow-sense heritability, h(2)) and dominant (delta(2)) genetic variance for 18 human complex traits. Within the same study base (10,682 Swedish twins), we calculated and compared the estimates from classic twin-based structural equation model with SNP-based genomic-relatedness-matrix restricted maximum likelihood [GREML(d)] method. Contributions of delta(2) were evident for 14 traits in twin models (average delta(2)(twin) = 0.25, range 0.14-0.49), two of which also displayed significant delta(2) in the GREMLd analyses (triglycerides delta(2)(SNP) = 0.28 and waist circumference delta(2)(SNP) = 0.19). On average, the proportion of h(SNP)(2)/h(twin)(2) was 70% for ADE-fitted traits (for which the best-fitting model included additive and dominant genetic and unique environmental components) and 31% for AE-fitted traits (for which the best-fitting model included additive genetic and unique environmental components). Independent evidence for contribution from shared environment, also in ADE-fitted traits, was obtained from self-reported within-pair contact frequency and age at separation. We conclude that despite the fact that additive genetics appear to constitute the bulk of genetic influences for most complex traits, dominant genetic variation might often be masked by shared environment in twin and family studies and might therefore have a more prominent role than what family-based estimates often suggest. The risk of erroneously attributing all inherited genetic influences (additive and dominant) to the h(2) in too-small twin studies might also lead to exaggerated "missing heritability" (the proportion of h(2) that remains unexplained by SNPs).